{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T16:32:46Z","timestamp":1784565166978,"version":"3.55.0"},"reference-count":39,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2008,10]]},"abstract":"<jats:p> Increased plasma and hepatic TNF-\u03b1 expression is well documented in patients with alcoholic hepatitis and is implicated in the pathogenesis of alcoholic liver disease. We have previously shown that monocytes from patients with alcoholic hepatitis show increased constitutive and LPS-induced NF-\u03baB activation and TNF-\u03b1 production. Our recent studies showed that chronic ethanol exposure significantly decreased cellular cAMP levels in both LPS-stimulated and unstimulated monocytes and Kupffer cells, leading to an increase in LPS-inducible TNF-\u03b1 production by affecting NF-\u03baB activation and induction of TNF mRNA expression. Accordingly, the mechanisms underlying this ethanol-induced decrease in cellular cAMP leading to an increase in TNF expression were examined in monocytes\/macrophages. In this study, chronic ethanol exposure was observed to significantly increase LPS-inducible expression of cAMP-specific phosphodiesterase (PDE)4B that degrades cellular cAMP. Increased PDE4B expression was associated with enhanced NF-\u03baB activation and transcriptional activity and subsequent priming of monocytes\/macrophages leading to enhanced LPS-inducible TNF-\u03b1 production. Selective inhibition of PDE4 by rolipram abrogated LPS-mediated TNF-\u03b1 expression at both protein and mRNA levels in control and ethanol-treated cells. Notably, PDE4 inhibition did not affect LPS-inducible NF-\u03baB activation but significantly decreased NF-\u03baB transcriptional activity. These findings strongly support the pathogenic role of PDE4B in the ethanol-mediated priming of monocytes\/macrophages and increased LPS-inducible TNF production and the subsequent development of alcoholic liver disease (ALD). Since enhanced TNF expression plays a significant role in the evolution of clinical and experimental ALD, its downregulation via selective PDE4B inhibitors could constitute a novel therapeutic approach in the treatment of ALD. <\/jats:p>","DOI":"10.1152\/ajpgi.90232.2008","type":"journal-article","created":{"date-parts":[[2008,8,8]],"date-time":"2008-08-08T00:45:21Z","timestamp":1218156321000},"page":"G718-G724","source":"Crossref","is-referenced-by-count":63,"title":["Enhanced PDE4B expression augments LPS-inducible TNF expression in ethanol-primed monocytes: relevance to alcoholic liver disease"],"prefix":"10.1152","volume":"295","author":[{"given":"Leila","family":"Gobejishvili","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirish","family":"Barve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swati","family":"Joshi-Barve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"McClain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199704103361506"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-112-12-917"},{"key":"R3","doi-asserted-by":"crossref","unstructured":"Draheim R, Egerland U, Rundfeldt C. 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